Late-Breaking Clinical Trial Abstracts

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The African-American Study of Kidney Disease and Hypertension (AASK)

Janice G Douglas for the AASK Study Group, Case Western Reserve University Medical School and University Hospitals of Cleveland, Cleveland, Ohio

AASK is a 3 x 2 factorial, NIDDK-sponsored trial that tested the effects of three antihypertensive regimens (initial therapy with ramipril, amlodipine, or metoprolol) and two different levels of blood pressure (BP) control (usual, mean arterial pressure [MAP] of 102–107 vs low, MAP ≤ 92 mmHg) on the progression of kidney disease from hypertension. Participants were 1094 African-Americans with hypertensive renal disease (glomerular filtration rates [GFR] between 20–65 ml/min/1.73m2), enrolled at 21 centers and followed for an average of 3–4 years. The primary outcome was change in GFR; the main secondary outcome was a composite of clinical endpoints (reduction in GFR of more than 50% or 25 ml/min/1.73m2, end-stage renal disease or death). Because the trial ended in mid-October, 2001, results are preliminary. The presence of even small amounts of proteinuria at baseline (urinary protein to creatinine ratio [UP/C] of >0.22 or ∼300mg protein/day) was associated with rapid progression of kidney disease. In most analyses, the level of proteinuria also influenced the effects of AASK treatments. The separation of MAP between the low and usual BP groups was 10 mmHg. Still, the usual and lower BP goals had similar effects to significantly delay hypertensive renal disease progression as compared to previous reports in the literature. For the comparison of medications, results were not definitive because the total GFR slopes and chronic slopes (3 m to end of follow-up) did not reach statistical significance in the same direction in all patients. However, important findings were evident. Ramipril as compared to metoprolol reduced the rate of decline in GFR by 25% and the rate of composite clinical events by 22% in all patients. In patients with baseline UP/C of >0.22, ramipril reduced the risk of clinical events by 46% as compared to amlodipine, while metoprolol reduced the risk of clinical events by 37% as compared to amlodipine. In summary, the usual BP goal (140/85 mm Hg during follow-up) was associated with substantial slowing of GFR decline as compared to prior observations in poorly controlled hypertensives. The lower than usual goal (127/77) was not associated with additional slowing in African Americans. Ramipril as compared to metoprolol appears to slow renal disease progression independent of protein level, while ramipril and metoprolol slow progression as compared to amlodipine in patients with baseline UP/C >0.22 (roughly ‘dipstick positive’ proteinuria).

In conclusion, AZ did not affect all cause mortality in recent post MI patients with low LVEF or in a subpopulation of patients at high mortality risk as defined by low HRV. Additionally, fewer patients developed AF/FL on AZ compared to PL. These data provide further support for the development of AZ as a treatment for AF/FL in patients with structural heart disease.

Improved Exercise Capacity Using a Novel pFOX Inhibitor as Antianginal Therapy: Results of the Combination Assessment of Ranolazine In Stable Angina (CARISA)

Bernard R Chaitman MD, for the CARISA Investigators.

Objectives: To determine the antianginal effect and tolerability of 12 wks treatment with ranolazine, a partial inhibitor of fatty acid oxidation, in chronic angina pts receiving atenolol 50 mg qd, or diltiazem CD 180 mg qd, or amlodipine 5 mg qd. Methods: CARISA randomized 823 pts with chronic angina on background antianginal therapy to a 3-arm parallel double-blind study of placebo, ranolazine 750, or 1000 mg bid stratified according to background therapy. Protocol entry required exercise-induced angina and ischemic ST segment depression ≥ 1mm (STD) within 3–9 min on a modified Bruce protocol. Exercise testing was performed 12 hrs post-dose (trough) after 2, 6, and 12 wks of double blind treatment and 4 hrs post-dose (peak) after 2 and 12 wks. The primary efficacy variable was exercise duration at trough at 12 wks (last observation carried forward). Secondary efficacy variables included exercise duration at peak, time to angina onset and STD at peak and trough, and angina frequency. Results: Ranolazine (both doses combined) at trough increased exercise time from baseline by 24±10 sec (P=0.012) vs placebo at wk 12; the increase was similar at 750 (P=0.03) and 1000 mg bid (P=0.029). At 12 wks, time to angina at trough was increased by 30±12 sec (P=0.014) and 26±12 sec (P=0.033) at the 750 and 1000 mg doses of ranolazine, respectively. Improvement in time to exercise-induced STD was slightly less (20 and 21 sec; NS). At 12 wks, ranolazine at peak significantly increased exercise time (P<0.02), time to angina (P<0.004), and time to STD (P<0.005). Increases in exercise time on ranolazine were greater on diltiazem or amlodipine than on atenolol; the differences were not statistically significant. Minimal effects on resting and exercise heart rate and blood pressure were observed. Angina frequency was significantly reduced by 0.8 and 1.1 episodes/wk at 750 mg (P=0.004) and 1000 mg (P<0.0001), respectively. Serious adverse events were observed in 6%, 7%, and 7% of pts on placebo, ranolazine 750 and 1000 mg bid. Minor side effects (dizziness, nausea, constipation or asthenia) were observed in <8% of pts. Small increases in QTc were observed at trough compared to placebo at 12 wks; 4.5 and 7.7 msec at the 750 and 1000 mg dose (P<0.001). Conclusions: Ranolazine is a new potentially effective antianginal drug for chronic angina patients who remain symptomatic on background calcium blocker or beta blocker therapy.

Canadian Antioxidant Restenosis Trial (CART-1)

Jean-Claude Tardif, MD

AGI-1067 (AtheroGenics) is a new vascular protectant which possesses strong antioxidant properties equipotent to those of probucol. Probucol has been shown to prevent restenosis after balloon angioplasty, but its pharmacokinetic and toxicity profiles are less than optimal. In a multicenter randomized trial, we studied whether AGI-1067 reduces restenosis as assessed by intravascular ultrasound (IVUS) after percutaneous coronary intervention (PCI) with or without stent placement. Methods and Results: Two weeks before PCI, 305 patients were randomly assigned to 1 of 5 treatment groups: placebo, probucol 500 mg BID, AGI-1067 70 mg, 140 mg, or 280 mg once daily. Patients were treated for 2 weeks before and 4 weeks after PCI. Baseline and 6-month follow-up IVUS were interpreted by a blinded core laboratory. Stents were used in approximately 81% of patients in all groups. Luminal area at the site of PCI was 2.66±1.58 mm2 for placebo, 3.69±2.69 mm2 for probucol, 2.75±1.76 mm2 for AGI-1067 70 mg, 3.17±2.26 mm2 for AGI-1067 140 mg, and 3.36±2.12 mm2 for AGI-1067 280 mg (P=0.02 for the dose-response relationship; P≤0.05 for both AGI-1067 280 mg and probucol vs placebo). There was also an increase from baseline to follow-up in lumen dimensions of the reference segments among the AGI-1067 140-mg and 280-mg groups (P=0.05 for 140 mg group vs placebo, P=0.077 for the AGI-1067 dose-response relationship). An increase in the QTc interval greater than 60 ms occurred in 4.8% of patients in the placebo group, 17.4% in the probucol group, and 4.8%, 2.4% and 2.5% in the AGI-1067 groups. Conclusion: The vascular protectant AGI-1067 and the antioxidant probucol reduce restenosis after PCI. In contrast to probucol, AGI-1067 also results in a dose-dependent improvement in lumen dimensions of the reference segments, which may represent the first clinical evidence of vascular protection it offers against the atherosclerotic process.

Antiarrhythmic drugs have been used with mixed results for the prevention and treatment of atrial arrhythmias that complicate the post-operative course of patients who have coronary artery bypass graft surgery (CABG). A major concern is the safety of continuing a membrane-active drug following hospital discharge. We assessed the efficacy and safety of a short course of propafenone (PFN), on the incidence and economic impact of atrial fibrillation after CABG. A total of 293 patients, mean age 63, 83% men were randomized prospectively at 7 sites. Patients with EF < 40%, Class IV CHF, recent infarction, or incomplete revascularization were excluded. Double-blind treatment consisted of placebo or PFN at a daily dose of 450 mg or 675 mg started within 24 hours of surgery and continued for the duration of hospitalization to a maximum of 15 days. The study endpoint was 5 minutes of AF. During the course of the study, 93% were dosed with digoxin and 84% were given beta-blockers. The main results are illustrated in the table. Discontinuations for adverse effects were approximately equal among the placebo and PFN groups, although cardiovascular adverse effects were slightly more common in the PFN groups including one death and one cardiac arrest. A short course of propafenone in moderate doses was effective and safe for preventing post-operative atrial arrhythmias and was more efficient than digoxin and beta-blocker in combination. This treatment benefit, however, did not translate into a reduced length of hospital stay.

While stents reduce restenosis compared to angioplasty, in-stent restenosis (ISR) due to smooth-muscle cell proliferation remains a problem with rates of 10–40% requiring approximately 100,000 repeat procedures annually. Proven treatment is currently limited to vascular brachytherapy. Prevention with drug-loaded stents to inhibit the pathological process is an attractive alternative. Paclitaxel is a chemotherapeutic agent that stabilizes microtubules by shifting the dynamic equilibrium between soluble and insoluble tubulin, inhibiting cell processes including mitosis, proliferation and migration while cells remain viable. ELUTES is a European multicentre, randomised, controlled, triple-blinded study evaluating the ability of the paclitaxel-coated V-Flex Plus coronary stent to reduce restenosis. The study included 4 progressive dose treatment groups and one control group (uncoated stent) in patients with discrete (<15 mm, type A/B1, >2.75 mm, <3.5 mm) lesions. Patients with severe calcification and tortuosity, left main lesions and multiple lesions in the target vessel were excluded. Study endpoints were percent diameter stenosis and late loss at 6 months measured by QCA, and MACE at 1 and 6 months with independent core lab QCA analysis and clinical events adjudication. Clopidogrel was given for 3 months. One hundred ninety-two (192) patients were enrolled, mean age 60±11 years, males 82.3%, diabetic 15.6%, hypercholesterolaemic 49.5%, and hypertensive 45.8%. Stented vessels were LAD (38%), RCA (35%), Circumflex (21%) and Ramus (5%). Lesions were mostly Type A (27%) or Type B1 (64%). Vessels were both mildly tortuous (45%) and mildly calcified (38%). Randomisation resulted in equal distribution between the control (38), low (37), medium-low (39), medium-high (39) and high (37) dose groups. Technical success was 99% (190/192). The highest dose density (2.7 μg paclitaxel/mm2 stent area) was found to be most effective. At 6 months, diameter stenosis and late loss were significantly less in the high dose (HD) group compared to control (14.2±4.1% vs 33.9±4.1% (P=0.007) and 0.10±0.12mm vs 0.73±0.12mm (P= 0.002)). This results in in-stent binary restenosis rates of 3.1% (n=1) vs 20.6%, respectively (P=0.055). The only target lesion revascularization in the HD group was for a lesion proximal to the stent. There were no differences in death (n=1 at day 0 in HD) and adjudicated non Q wave infarcts (n=2 in HD group and 1 in control, all within day 1 and associated with acute dissection) with no late stent thromboses. Paclitaxel-coated stents effectively inhibit restenosis and are as safe as uncoated stents.

The Effects of Treating Depression and Low Social Support on Clinical Events After a Myocardial Infarction

The Enhancing Recovery in Coronary Heart Disease Patients Study was a randomized clinical trial to determine whether treating depression and low social support reduces mortality and recurrent infarction following myocardial infarction (MI). Patients (n = 2481) who met criteria for either major or minor depression and/or low social support were recruited within 28 days of the index infarction and randomized to psychosocial intervention (PI) or usual medical care (UC). The intervention was a series of individual and group cognitive-behavioral therapy sessions delivered over six months with adjunctive pharmacotherapy for depression, when indicated. Although a statistically significant improvement in depression and low social support was observed, no significant differences in clinical endpoints were found over the average 41-month follow-up between the PI and UC groups (303 UC patients [24.4%] and 299 PI patients [24.2%] died or had a non-fatal MI). No differences in outcomes were found among the three psychosocial risk groups (patients who met criteria for depression only, low social support only, or both) or by major demographic subgroups according to pre-planned analyses. Four possible explanations for these findings are considered: (1) Treatment for depression or low social support delivered immediately following MI may not be effective for reducing risk for mortality or recurrent infarction, either because the treatment does not alter the underlying risk, or because (2) treating depression and low social support in the immediate post-MI period may not reduce psychosocial risk rapidly enough to have an appreciable effect on mortality or recurrent infarction. (3) Depression and social isolation substantially improved in the UC group, resulting in smaller than expected differences in depression and social support between the PI and UC groups. This may have been due to patients in the UC group receiving psychological or other help on their own, or because patients with transiently depressed mood or social isolation were enrolled. (4) The intervention may not have been delivered as effectively as intended; many patients may have lacked readiness or motivation or were unable to participate fully in therapy. Further research is needed to identify the most effective modalities and optimal timing for treating depression and poor social support, especially in medically vulnerable populations.

Randomised Trial of Cholesterol-Lowering Therapy and of Antioxidant Vitamins in 20,536 people at Increased Risk of Coronary Heart Disease Death

The Heart Protection Study assessed the effects of cholesterol-lowering therapy and of antioxidant vitamin supplementation in various patient categories for which there had been uncertainty about the value of such treatment. Patients aged 40–80 with a history of occlusive vascular disease or diabetes were eligible provided their own doctors did not consider statin therapy clearly indicated. Between July 1994 and May 1997, 20,536 patients were recruited in 69 UK hospitals. Previous MI was reported by 8510 (most of whom were elderly, female or had “low” cholesterol levels) and some other CHD by 4876. Among the 7150 with no history of CHD, 1820 reported a previous stroke or TIA, 2701 some other peripheral artery disease, and 3982 diabetes (with overlap between these categories). There were 5082 women and 15,454 men, with 4893 aged 65–69 and 5804 aged 70–80. Total cholesterol was <5.0 mmol/l (194 mg/dl) in 4072, and LDL cholesterol was <3.0 mmol/l (116 mg/dl) in 6793. Participants were randomly allocated simvastatin 40 mg daily or matching placebo for 51/2 years. On average during the study, about 15% of participants allocated simvastatin stopped taking statin therapy and about 20% of those allocated placebo started taking it, yielding an average LDL cholesterol difference of 1.0 mmol/l (39 mg/dl). Using a factorial design, half of each treatment group was also randomly allocated antioxidant vitamins (600 mg E, 250 mg C, 20 mg beta-carotene daily) and half allocated placebo. Preliminary analyses involve confirmed and (as yet) unrefuted reports of non-fatal MI or CHD death (“total CHD” events) in 2148 participants, non-fatal or fatal stroke in 1069, “major vascular events” (total CHD, total stroke or any revascularisation) in 4648, cancer (excluding non-melanoma skin) in 1636, and 2831 deaths. The vitamins did not produce any beneficial or adverse effects on vascular or non-vascular morbidity or mortality in this population. Cholesterol-lowering therapy reduced total and vascular mortality, total CHD, stroke, and revascularisation procedures, with no good evidence of any effect on non-vascular mortality or cancer. Myopathy was reported in <0.1% of participants. After making allowance for non-compliance (including non-study statin use), simvastatin 40 mg daily produced reductions in “major vascular events” of at least one-third in a very wide range of high-risk patients for whom there had previously been uncertainty about using cholesterol-lowering therapy (including women, people aged over 70, those with LDL below 3.0 mmol/l, and those with diabetes or noncoronary occlusive disease without pre-existing CHD).

IONA: Nicorandil for Stable Angina

Chronic stable angina is a common condition which affects approximately 1 in 10 people over the age of 60 years and, therefore, at least 5 million Americans. It significantly impairs quality of life and is not benign with a rate of major coronary events which ranges from 3 to 20% per annum. IONA (Impact Of Nicorandil in Angina) is the first large scale randomised controlled trial to be reported of the effects of a specific anti anginal agent on clinical outcome in patients with chronic stable angina. Nicorandil improves the balance of myocardial oxygen demand and supply through arteriolar and venous dilation and improvement of coronary bloodflow which is due to both a potassium (K+) channel opening and a nitrate effect. Experimentally it has also been shown to facilitate a natural cardioprotective process called ischaemic pre-conditioning whereby an episode of myocardial ischaemia renders the myocardium more resistant to subsequent episodes of ischaemia. It has been available in Europe and Japan for several years. Patients with stable angina pectoris and higher risk features including previous MI, CABG, LV dysfunction and hypertension were randomised to nicorandil 10mg increasing to 20 mg twice daily or identical placebo. Patients were receiving other regular anti anginal and coronary preventive medications including nitrates (86%), beta blockers (56%), calcium channel blockers (55%), aspirin (88%), statins (57%) and ACE inhibitors (29%). The trial was conducted exclusively in the United Kingdom where, In total, 5126 patients were recruited who were then followed for up to 3 years (average 1.6 years). The primary end point, which was a composite of coronary heart disease death, non fatal myocardial infarction or unplanned hospitalisation for cardiac chest pain was significanly reduced by nicorandil (HR 0.83, 95% CI 0.72, 0.96), P = 0.014), reflecting a 17% reduction in risk. The secondary end point, coronary heart disease death or non fatal MI showed a strong trend to reduction (HR 0.79, 95% CI 0.61, 1.02), P = 0.068), reflecting a 21% reduction in risk. In summary, nicorandil reduced the incidence of major coronary events in patients with chronic stable angina and is, therefore, the first specific anti anginal medication for which an improvement in clinical outcome has been demonstrated.

Objectives: To assess in patients with Acute Coronary Syndromes without ST segment elevation the dose-response relation of 4 dose levels of fondaparinux (2.5, 4, 8, 12 mg od) in comparison with enoxaparin (1 mg/kg, bid), with respect to the occurrence of death, myocardial infarction and recurrent ischemia as well as with respect to safety (bleeding). Methods/Patients: 1147 patients were enrolled in 66 hospitals in 5 European countries. For efficacy, data for 929 patients who had at least 12 hours continuous 12 lead ECG recording and no protocol violations are presented. Male 67%, age 62 years (24–89), ECG abnormalities at enrollment 80%, elevated cardiac troponin 41%.

Conclusion: Overall, fondaparinux od is at least as effective and as safe as enoxaparin bid in the doses tested. No clear dose-response was obtained. Results were consistent (data not shown) for different endpoint definitions, and different patient groups, including per protocol analysis (see above) and all patients randomized and treated. Best results were achieved with the lowest dose fondaparinux (P < 0.05 vs Enoxaparin at day 9 and day 30). Further phase III studies of fondaparinux in patients with Acute Coronary Syndromes are warranted.

A Clinical Trial of an Educational Intervention to Achieve Recommended Cholesterol Levels Among Patients With Coronary Artery Disease

Background: Despite national efforts to improve cholesterol management, many patients are not reaching national cholesterol targets. Studies have indicated that patient education by nurses can have dramatic effects on increasing patient adherence to medical regimens and improving outcomes. We sought to determine if a nurse-based program designed to educate patients about cholesterol targets (with an emphasis on LDL) and management could increase one-year adherence with National Cholesterol Education Program (NCEP) guidelines. Methods: We randomized 756 patients hospitalized at Yale-New Haven Hospital with coronary artery disease to usual care or an educational intervention that included monthly educational mailings and quarterly scheduled phone contacts. At each phone contact the patient was engaged in a discussion about their cholesterol levels and received information about their target goals. Patients were encouraged to discuss their target goals with their physician, but the nurse did not contact their clinicians. The primary outcome was adherence with the NCEP cholesterol treatment guideline (LDL ≤ 100 mg/dL) one-year after the index hospitalization. Results: A total of 375 patients were assigned to the intervention and 381 to usual care. The groups did not differ in terms of baseline characteristics, and had a mean age of 63 and 64 years respectively. About 5% of each group had correct baseline knowledge of LDL targets. Of the 575 patients for whom a cholesterol measurement was obtained on the day of admission, 44% of the intervention group and 41% of the usual care group had an LDL ≤ 100 mg/dL. We completed follow-up for 89% of the patients (90% of intervention group and 87% of usual care group). Adherence with the NCEP guideline at one-year did not differ between the educational intervention group and the usual care group (70% versus 67%, P=0.46). At follow-up, patient knowledge about the LDL target level was higher for the intervention group compared with the usual care group (20% versus 7%, P=0.001).

Conclusions: Our aggressive educational intervention failed to increase the proportion of patients who reached their target LDL levels. Patient knowledge of LDL cholesterol targets improved substantially in the intervention group, but still remained disappointingly low. The proportion of patients reaching target at one-year in both groups was higher than anticipated. Patient education alone using this approach is unlikely to further increase the rate of patients meeting LDL targets. Future efforts may be directed toward strategies that integrate interventions for the patient and the clinicians.

Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH)

Background: Implantable left ventricular assist devices (LVADs) have recognized benefit in end stage heart failure patients as a “bridge” to cardiac transplantation, but their ultimately intended value in enhancing survival and quality of life as a long-term therapy has not been evaluated. Methods: We randomly assigned 129 patients with chronic end-stage heart failure who were ineligible for cardiac transplantation to LVAD implantation (Thoratec VE Heartmate; n=68) or optimal medical management (OMM; n=61). All patients had a left ventricular ejection fraction of ≤ 25%, NYHA Class IV heart failure symptoms, and either intravenous inotropic drug dependence or reduced peak VO2 (9.18±1.98 ml/kg/min). We hypothesized a 33% reduction in relative risk (RR) of all-cause mortality in the LVAD group over a two-year observation period, without a decrement in quality of life. Results: Kaplan-Meier survival analysis (primary endpoint) showed a 48% reduction in RR of all cause mortality in the LVAD group (RR = 0.52 (0.34–0.78; P=0.001). The probabilities of one and two-year survival were 52.1% vs 24.7% (P=0.002) and 22.9% vs 8.1% (P=0.09) in LVAD and OMM patients, respectively. The frequency of serious adverse events was 2.35 (1.86–2.95) times greater in the LVAD group with a predominance of infection, bleeding, and device malfunction. Quality of life, as measured by the SF-36, the Beck depression inventory and NYHA functional classification, was significantly improved in the LVAD group at one year. Conclusions: We have documented clinically meaningful survival benefit and improved quality of life using a wearable LVAD in the treatment of advanced heart failure. These results establish LVADs as a new myocardial “replacement” therapy, joining transplantation in the treatment armamentarium for end-stage heart failure.

The PRESTO Trial (Prevention of Restenosis with Tranilast and its Outcomes)

David R. Holmes, Jr, MD, Mayo Clinic, 200 First St SW, Rochester, MN

Purpose: To compare the frequency of major adverse cardiovascular events (MACE) in patients treated with tranilast to that of placebo over an observation period of nine months in patients who have undergone a successful percutaneous coronaryintervention (PCI). Design: Double-blind, randomized placebo controlled 9 month trial. Patients were assigned to receive one of 5 regimens begun 4–8 hours after successful PCI: tranilast 300 or 450 mg bid, administered for 1 or 3 months or placebo. The primary efficacy parameter was the MACE composite of death from any cause, myocardial infarction, or ischemia-driven target vessel revascularization at 9 months. Secondary endpoints included core laboratory angiographic and IVUS parameters. Population studied: 11,488 patients 18 years or older who had a successful PCI for single or multiple vessel coronary artery disease from April, 1999 to July, 2000. A successful PCI was defined as at least one vessel dilated to <50% stenosis with no evidence of a myocardial infarction prior to dosing. Outcome: PRESTO subjects were representative of typical PCI patients presenting with symptomatic coronary artery disease. For example, nearly 25% had Type 2 diabetes, 62% had hypertension, 66% had high cholesterol and nearly 40% had suffered a previous MI. The outcome data showed that 15–16 percent of patients in each of the treatment arms experienced a MACE. The 9 month cumulative risk as estimated by Kaplan-Meier method showed no difference between the placebo and tranilast treated groups. Conclusion: Tranilast did not meet its efficacy targets, but PRESTO results provide valuable data about the current practice of interventional cardiology and the frequency, natural history, and clinical, angiographic and IVUS characteristics of restenosis in the modern treatment era.